Cigarette smoking and infertility

de Mouzon Jacques, MD, MPH, INSERM U822, Le Kremlin-Bicêtre, France

Introduction Cigarette smoking associated to many pathologies

Cancer : Lung, Stomach, Bladder, etc. Cardiovascular disease, lung insufficiency, etc. First cause of preventable mortality in France (65000 deaths)

Among women, well established role in pregnancy Pre-eclampsia,, Placenta praevia, Abruptio placentae Fetus : birth weight (150-200g), small for gestational age

Increasing concern in human reproduction For natural fertility (woman and man) For ART

Several hypotheses for action mode

I / Natural fertility

Normal fertility On average, 85% of couples conceive within 12

months 90 % within 18 months What about cigarette smokers ?

de Mouzon J, Spira A, Schwartz D. Int J Epidemiol 1988,17:378-384

Diminution of probability to conceiveFrench study (Gefco)

0102030405060708090

1 2 3 4 5 6 7 8 9 10 11 12 Cycles

%SmokersNon smokers

1887 couples, planned pregnancies

Increase in TTPEuropean study (7 countries)

0

5

10

15

20

25

30

35

0 1 à 10 ≥ 11

Population

Maternityhospitals

Cigarettes / day

%

Bolumar F, Olsen J, Boldsen J et al. Am J Epidemiol 1996,143:578-587

* **

Infertility duration multiplied by : 1.2 pour 1 - 10 cigarettes (1.1-1.4) 1.5 pour > 10 (1.3-1.8)

General population : 3187 planned pregnanciesMaternity hospitals : 2587 planned pregnancies

TTP > 9,5 months

Increase in TTP (2)England (Avon county)

05

10152025303540

Nonsmokers

1 to 4 5-9 10-14 15-19 ≥ 20

> 6 months > 12 months Linéaire (> 12 months) Linéaire (> 6 months)

Passivecigarettes / day

8515 planned pregnancies

Hull MGR, North K, Taylor H et al. Fertil Steril 2000,74:725-733

%

Increased risk of TTP≥ 12 months Male and female smoking

0

0,5

1

1,5

2

2,5

NonSmoker

1 to 4 5 to 9 10 to 14 15 to 19 ≥ 20

Woman Man cigarettes

8515 planned pregnancies

Hull MGR, North K, Taylor H et al. Fertil Steril 2000,74:725-733

English study

Male and female smokingCanadian study

Woman’s smoking

Man’s smoking No Yes

No 1.00 0.95 (0.84 - 1.07)

Yes 0.91 (0.83 - 1.00) 0.77 (0.68 - 0.85)

Woman +, Man +, Both man and woman ++

OR for fecundibility

Curtis KM, Savitz DA, Arbuckle TE Am J Epidemiol 1997,146:32-41

Ontario Farm Family Health Study:2607 planned pregnancies

In utero exposition to smokingOdds-ratios for fecundibility

Woman Woman’s mother OR CI 95%

Non smoking Non smoking 1.00 ---

Smoking 0.70 0.48-1.03

Smoking Non smoking 0.67 0.42-1.06

Smoking 0.53 0.31-0.91

Jensen TK, Henriksen TB, HjollundNHI et al. Am J Epidemiol 1998,148:992-997

Prospective study, CO stopping, 423 couples, multivariate analysis

In utero exposition to smoking Danish study (2)

Jensen et al, Int J Androl. 2006 National cohort of twins born 1931 - 1952

1653 women / 1598 men, with TTP Exposition in utero to cigarette smoking

Fecundibility Odds Ratios, whole cohort Women : FOR = 0.81; 95% CI 0.67-0.99 Men : FOR = 1.12; 95% CI 0.89-1.40 NS

Selection of twins of opposite sex Women : FOR = 0.65; 95% CI 0.47-0.91 Men : FOR = 0.97; 95% CI 0.60-1.55

Cigarette smoking and female fertilityOther aspects

Increase in short / irregular cycles Younger menopausal age (2 years) Increase % of early menopauses (<40 yrs)

Related to level and duration of smoking Multiplied by 3 fo 20 cig / day, 20 years ± reversible

Willett W, Stampfer MJ & Bain C et al. Cigarette smoking, relative weight, and menopause. Am J Epidemiol 1983,117: 651-8

Cigarette smoking and male fertilitySemen

Künzle 2003, infertile smokers Non smokers p n 655 1131 Concentration : 68 (66) 80 (75) 0.001 Motility A : 37.1 (18.6) 38.7 (17.7) 0.07 Normal forms: 21.2 (14.6) 23.7 (15.5) 0.001

Trummer 2002, infertile: n=478 517 109 ExS Round cells (106) : 3.5 (5.3) 2.7 (3.4) 2.6 (3.4) 0.01

Saleh 2002 12 Infert S 21 Infert NS 13 Donors NSLeucocytes (106) 1.8 (0.6-4.4) 0.0 (0.0-0.4) 0.1 (0.0-0.2) 0.01

S=Smokers; NS=Non Smokers; ExS= Ex Smokers

II / Assisted Reproduction

Woman cigarette Smoking and IVF. Retrospective cohort

Non Smoker

(n=351)

Ex Smoker

(n=111)

Smoker

(n=37)

Age 32.9 33.8 31.5

E2 2297 2097 1728*

oocytes 15.4 15.1 14.0

Fertilization rate 54.1 54.1 49.9

Transf Embryos 3.6 3.5 3.6

Implant R (%) 16.4 15.9 6.7*

Van Voorhis BJ, Dawson JD, Stovall DW et al. Obstet Gynecol 1996;88:785-791

Woman cigarette Smoking and IVF. Tubal infertility

Non Smoker

≤ 20 (n=351)

Passive Smk

20-50 (n=111)

Smoker>50 (n=37)

Age 32.5 32.7 32.4

E2 1658 1738 981*

Oocytes 5.4 5.4 5.5

Fertilization rate 67.6 57.7 67.9

Transf Embryos 2.4 2.5 2.3

Pregnancy (%) 32.6 33.3 32.9

Smoking classified according to follicular cotinine (ng/ml)Sterzik K, Abt M, Strehler E et al. Human Reprod 1995,10:3213-3217

Woman cigarette Smoking and oocyte quality

Smoking

No

(n=102)

Passive (n=21)

< 15 cig/D (n=37)

≥ 15 cig/D

(n=37)

Age 33.8 32.1 32.2 32.4

Oocytes 10.2 9.5 8.0 7.3*

Fertilization rate 37 47 46 34

Fixed oocytes %

37.8 27.7 55.0 54.1

Diploid (%) 5.1 13.0 12.1 21.1

Zenzes MT, Wang P, Casper RF (Human Reprod 1995,10:3213-3217

Couple cigarette smoking and IVF failure OR

Failure risk

Smoking status Pregnancy Live birth

Both no smoker 1.00 1.00

Couple smoker 2.41 (1.07-5.45) 3,76 (1.40-10.0)

Woman smoker 2.71 (1.37-5.35) 2.51 (1.11-5.67)

Year of smoking 1.09 (1.01-1.16)

Klonoff-Cohen H., Natarajan L., Marrs R., Yee B. Human Reprod 2001,16 :1382-1390

N=221

Woman cigarette smoking and Pregnancy rate

Belaisch-Allart J, El-Akoum ., Mayenga JM, et al. Fertil Steril 1996,66:679-689

Cigarette smoking

No < 10 cig / D ≥ 10 cig / D

OPU 842 133 206

Pregnancies (%) 21.1 20.3 15.1*

Woman passive cigarette smoking and Pregnancy rate

Non Smoker (146)

Passive smoker (40)

Smoker (39)

Age 34.6 (4.0) 33.5 (3.4) 33.6 (3.8)

Ampoules 32.4 (14.9) 30.2 (16.2) 29.2 (14.2)

E2 (pmol/l) 7316 (3721) 7921 (4179) 7142 (3388)

Oocytes 11.1 (5.7) 11.5 (5.6) 11.3 (5.3)

M2 oocytes (%) 77.0 (17.0) 78.0 (18.0) 80.0 (1.0)

Neal MS, Hughes EG, Holloway AC et al. Hum Reprod 2005,20:2531-5 All NS

Woman passive cigarette smoking and Pregnancy rate (2)

Non Smoker (146)

Passive smoker (40)

Smoker (39)

Fertilization rate 63 58 57

Transf. embr 2.3 (0.9) 2.2 (0.5) 1.9 (0.8)

CES* 12 (4) 10 (4) 12 (5)

PR/OPU (%) 48.3** 20.0 19.4

Implantation (%) 25.0** 12.6 12.0

Neal MS, Hughes EG, Holloway AC et al. Hum Reprod 2005,20:2531-5

•Cumulative embryo score•** p<0.05

Cigarette smoking and implantation: oocyte donation

Pregnancy rate according to

smokingNo 1 - 10

cig/j>10 cig/j

Donor (n) 49.9 (401) 52.6 (384) ---

Recipient(n) 51.6 (680) 59.0 (n=61) 34.1 (44)*

S.R.Soares, Human Reproduction 2006785 oocyte donations, Valence, man no-smoker, transfer D32.1 embryos on average (identical in the groups)

*: p<0.05

Meta-analysis 1 (EG Hugues)

13 studies on natural fertility (n=55000) All odds-ratios or relative risks of fertility lower

than 1 except 1 : from 0.3 to 1 7 studies on ART (n=1700)

All odds-ratios of fertility lower than 1 Mean estimate, 0.57 (0.42-0.78)

Hugues EG, Brennan BG. Fertil Steril 1996,66:679-689

Meta-analysis 2 (Augood)

13 studies on natural fertility Mean estimate of risk of infertility among smokers:

OR =1.60 (1.34-1.91) Mean estimate of risk of TTP >1yr among smokers

OR = 1.42 (1.27-1.58)

9 studies on ART Mean estimate of risk pregnancy among smokers

OR = 0.66 (0.49-0.88)

Augood C, Duckitt K, Templeton. Human Reprod 1998,13 :1532-1539

Cigarette smoking and infertility Hypotheses

Nicotine Hypothalamo-pituitary-ovarian axis

Early menopause, Estradiol, oocytes number local :

cervical mucus, tubal motility, ciliary function

Other compounds :Cadmium (diploid oocytes ?) Hypoxia: oxydative stress on follicle Marker for tubal infertility

Van Voorhis BJ et al. Tubal infertility in IVF cohort : No smoker 34 %, Ex smoker 57 %, smoker 62 %.

Smoker more sexually active (ACSF)

Conclusion (1)

Decreased fertility (natural and ART)

Probable causal relationship Relation dose-effect, duration-effect Biological plausibility Reversibility at stopping (±)

Some interesting points In utero exposure Probable maternal and paternal effect Passive exposition

Conclusion (2)

Methodological difficulties in measuring exposition Questionnaires, but concealed exposures Biological measurements (cotinine) , expensive Difficulties to measure duration, level Carbon monoxyde tester in expired air

No study with large sample in ART

Conclusion (3)French epidemiological study

Objective: association smoking/ Result

Large cohort study (3500 couples) 14 ART Centres Measurement of carbon monoxyde Both members of couples Criteria

Sperm quality Oocyte number and quality Cycle result and pregnancy outcome